The present invention concerns a process for the production of implants with an ultrahydrophilic surface as well as the implants produced in that way and also processes for the production of loaded, so-called bioactive implant surfaces of metallic or ceramic materials, which are used for implants such as artificial bones, joints, dental implants or also very small implants, for example what are referred to as stents, as well as implants which are further produced in accordance with the processes and which as so-called “delivery devices” allow controlled liberation, for example by way of dissociation, of the bioactive molecules from the implant materials.
The implantation of artificial joints or bones has become of increasing significance in recent years, for example in the treatment of joint dysplasias or luxations or in the case of diseases which can result from the wear of joints as a consequence of joint misplacements. The function of the implants and the materials which are used for the manufacture thereof and which, besides metals such as titanium or metal alloys, can also include ceramic or plastic materials such as Teflon or polylactides, are being continuously improved so that after a successful healing progress in 90-95% of cases implants can have lives of 10 years.
Irrespective of those advances and improved operative methods, implantation is still a difficult and burdensome intervention, in particular as it is linked to a tedious healing process for the implant, which often includes clinic and cure treatment stays of months in length, including rehabilitation measures. Besides the pains in that respect the length of the treatment period and the fact of being taken out of familiar surroundings represent major stresses for the patients concerned. In addition the tedious healing process gives rise to high levels of personnel and nursing costs due to the intensive care required.
Knowledge of the processes at the molecular level, which are required for an implant to successfully grow in place, has become significantly enlarged in recent years. Structure compatibility and surface compatibility are crucial for tissue compatibility of an implant. Biocompatibility in the narrower sense is governed solely by the surface. Proteins play a crucial part at all levels in integration. As explained hereinafter they already decide during the implantation operation, due to the formation of an initial adsorbed protein layer, about the further progress in terms of implant healing as the first cells are later established on that layer.
In the molecular interaction between implant which is also referred to as biomaterial and tissue, a large number of reactions occur, which seem to be arranged in a strictly hierarchical fashion. The adsorption of proteins at the surface of the biomaterial takes place as the first biological reaction. Then, in the protein layer which is produced as a result, individual protein molecules are transformed for example by conformation changes to signalling substances which are presented on the surface, or protein fragments acting as signalling substances are liberated by catalytic (proteolytic) reactions.
Triggered by the signalling substances, in the next phase cellular colonisation takes place, which can include a large number of cells such as leucocytes, macrophages, immunocytes and finally also tissue cells (fibroblasts, fibrocytes, osteoblasts, osteocytes). In that phase other signalling substances, so-called mediators such as for example cytokines, chemokines, morphogens, tissue hormones and genuine hormones play a crucial part. In the case of biocompatibility the situation finally involves integration of the implant in the overall organism and ideally a permanent implant is achieved.
In the light of works which have been carried out in recent years at the molecular level of osteogenesis, chemical signalling substances, the so-called “bone morphogenic proteins” (BMP-1-BMP-15) which influence bone growth have become of increasing significance. BMPs (in particular BMP-2 and BMP-4, BMP-5, BMP-6, BMP-7) are osteoinductive proteins which stimulate bone regeneration and bone healing insofar as they cause proliferation and differentiation of precursor cells to give osteoblasts. In addition they promote the formation of alkaline phosphatases, hormone receptors, bone-specific substances such as collagen type 1, osteocalcin, osteopontin and finally mineralisation.
In that respect the BMP molecules regulate the three key reactions of chemotaxis, mitosis and differentiation of the respective precursor cell. In addition BMPs play an important part in embryogenesis, organogenesis of the bone and other tissue, in which respect osteoblasts, chondroblasts, myoblasts and vascular smooth muscle cells (proliferation inhibition by BMP-2) are known as target cells.
In the meantime 15 BMPs inclusive of multiple isoforms are known. Except for the BMP-1 the BMPs belong to the “transforming growth factor beta” (TGF-β) superfamily, for which specific receptors are detected on the surfaces of the corresponding cells. As the successful use of recombinant human BMP-2 and/or BMP-7 has shown in experiments concerning defect healing processes on rats, dogs, rabbits and monkeys, there does not appear to be any species specificity.
Previous attempts to utilise the bone growth-triggering properties of the BMPs specifically for implantation purposes, by the BMP-2 and/or BMP-7 being applied directly to metallic or ceramic biomaterials have however been substantially unsuccessful.
A series of works in the field of coated implant materials is known in the state of the art. Thus WO9926674 describes a process for the production of bioactive implant surfaces of metallic or ceramic materials, in which in a first step anchor molecules are covalently bonded to the surface of the implant material and in a second step peptides are covalently bonded to the anchor molecules.
WO0209788 provides a process for the production of bioactive implant surfaces of metallic or ceramic materials, in which in a first step anchor molecules with hydrophobic residues are covalently bonded to the surface of the implant material and in a second step peptides are applied to the implant material treated in that way, which are immobilised as a consequence of non-covalent interactions between the peptides and the hydrophobic residues of the anchor molecules.
In accordance with those two documents it is therefore necessary to chemically immobilise on the surface of the implant anchor molecules which are then covalently chemically bonded to the peptides or which are bonded on the implant surface as a result of non-covalent interactions. Test results by the inventors have shown in that respect that attempts to immobilise peptides on the implant surface without anchor molecules were not successful.
It was now found by the inventors surprisingly, in particular in regard to those earlier attempts on the part of the inventors to implement immobilisation, that immobilisation of peptides on metal surfaces, in particular growth factors of the TGF class, for example BMP proteins, can be achieved if a sufficiently hydrophilic surface can be provided on the implant material. It was found by the inventors that this can be achieved if an ultrahydrophilic oxide layer is produced on the metal surface by treatment with an oxidation agent.
In that respect the invention makes use of the fact that surfaces with a high surface energy can have strong tissue bioadhesion. As surfaces with a high surface energy generally have low contact angles with water, such a surface can be very easily identified by way of the measurement of dynamic contact angles. Small contact angles characterise a high level of wettability of a surface.
In respect of the dynamic contact angles a distinction is drawn between an advancing angle (θA) and a receding angle (θR) and the difference in those angles is referred to as contact angle hysteresis. In that respect the advancing angle is characteristic of the hydrophilicity-hydrophobicity properties of a surface and substantially corresponds to what is referred to as the static contact angle. The greater the degree of hysteresis, the correspondingly greater is generally the heterogeneity of the surface. Mechanically polished or electro-polished titanium surfaces normally have dynamic contact angles (advancing angle) of 70-80° and in accordance with pertinent literature have a low tissue bioadhesion. Therefore in accordance with the inventors' development it is desirable to also provide surfaces with low contact angles on metals.
According to the invention surfaces with dynamic contact angles of between 0 and 10° are defined as “ultrahydrophilic”. They have at the same time a characteristic nanostructure. In works involving animal experiments it was possible to show on the part of the inventors that bone density is twice as high after 4 weeks in the environment of an ultrahydrophilic implant, as in the environment of the control implant.
Admittedly the state of the art in accordance with EP 1 150 620 already described implants with hydrophilic surfaces after sand blasting and acid etching, on which wetting angles with water of between 20-50° were measured. Such surfaces are referred to as “hydrophilic” and could be preserved in given saline solutions. It will be noted however that it was observed in accordance with EP 1 150 620 that such surfaces were sensitive in relation to a rising salt concentration.
It has further been known in the state of the art for many years that hydrophilic metal surfaces, for example of titanium, are not stable but spontaneously become hydrophobic again. The chemical state of the surface of titanium and titanium-based alloys is complex. It is assumed that the surface of titanium metal oxidises spontaneously in air and water and that a reaction then occurs with water at the surface, that is to say in the outermost atom layer of the oxide, with hydroxyl groups being formed.
Accordingly such surfaces are particularly sensitive in relation to gamma sterilisation, a method which nowadays is widely used in the production of implants which can be clinically employed. Thus it was shown in the state of the art that titanium dioxide layers can be rendered hydrophilic by light irradiation. Those layers also lose their hydrophilicity after just a short time and become hydrophobic again, in which respect the precise mechanism in that change is still obscure.
Accordingly there is a need for a process which permits the production of implants which have unlimitedly stabilised ultrahydrophilic layers thereon and which at the same time withstand sterilisation.